Prostate cancer (CaP) is the second leading cause of cancer-related death in American men. Recent advances in the management of advanced disease with chemotherapy androgen synthesis inhibitors have begun to improve outcomes; however, many challenges remain. The etiology of CaP remains unknown. It is not clear why the prostate is so susceptible to oncogenesis and why its formation is associated with chronic infection. The contribution of epigenetic alteration in CaP development also remains poorly defined. Why do malignant cancers develop without clear signs of chromosomal level changes? Finally, how do tumors become resistant to the newest forms of chemotherapy and androgen inhibition? This Collaborative Research in Tumor Microenvironment UOl application is built upon the long term collaboration between Drs. Wu and Witte, and more recent studies involving the Nelson laboratory, and the synergies between the UCLA CaP Challenge Award, entitled Defining targets and biomarkers in CaP stem cells: New therapeutic opportunities (2008-2011) and Fred Hutchinson Cancer Research Center/University of Washington TMEN U54 program, Significance of microenvironment for CaP initiation and progression (2007-2012). Building upon these efforts, we will now jointly address the critical questions involving Influences of microenvironment on cancer stem cells. Specifically, we focus on the role ofthe tumor microenvironment in controlling proliferation and transformation of normal prostate stem cells and on the role of the tumor microenvironment in causing CaP stem cells to develop resistance to current therapies. The first question, studied in Aim 1, has significant implications for cancer prevention, since strategies to reduce inflammation and infection could inhibit entry of normal stem cells into the cell cycle. This Aim will also shed light on the mechanisms through which immune tolerance is established and how to sensitize CaPs to immune therapies. The second question, studied in Aim 2, has implications for expanding our understanding ofthe landscape of cancer stem cells and shifts our therapeutic strategy from cancer cell and gene-based target to pathway oriented approaches. Our Specific Aim 3 is designed to address the final question how cancer therapies can change the benign cellular constituents associated with neoplastic cells and causes CSC expansion and tumor repopulation.